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A Factor IX Gene Therapy Study (FIX-GT) (FIX-GT)

Primary Purpose

Hemophilia B

Status
Terminated
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
FLT180a
Sponsored by
University College, London
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hemophilia B

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)MaleDoes not accept healthy volunteers

Inclusion Criteria:

  1. Adults males, ≥ 18 years of age;
  2. Confirmed diagnosis of HB defined as one of the following:

    Documented severe FIX deficiency with plasma FIX activity of <1% of normal or moderately severe FIX deficiency with plasma FIX activity level between ≥1% and ≤2% and a severe bleeding phenotype defined by one of the following:

    1. On prophylaxis for a history of bleeding, or
    2. On-demand therapy with a current or past history of 4 or more bleeding episodes/year, or
    3. Evidence of chronic haemophilic arthropathy (pain, joint destruction, and loss of range of motion).
  3. Able to give full informed consent and able to comply with all requirements of the trial including 15-year long-term follow-up;
  4. Willing to practice barrier contraception until at least two consecutive semen samples after vector administration are negative for vector sequences;
  5. Lack of neutralising anti-AAV antibodies using an in-vivo transduction inhibition assay;
  6. At least 150 exposure days to FIX concentrates.

Exclusion Criteria:

  1. Presence of neutralising anti-human FIX antibodies (inhibitor, determined by the Bethesda inhibitor assay) at the time of enrolment or a previous history of FIX inhibitor;
  2. Patients at high risk of thromboembolic events (high risk patients would include those with a history of arterial or venous thromboembolism (e.g. deep vein thrombosis, pulmonary embolism, non-haemorrhagic stroke, arterial embolus) and those with acquired thrombophilia including conditions such as atrial fibrilation);
  3. Use of investigational therapy for haemophilia within 30 days before enrolment;
  4. Patients with active hepatitis B or C, and HBsAg or HCV RNA viral load positivity, respectively, or currently on antiviral therapy for hepatitis B or C. Negative viral assays in 2 samples, collected at least 6 months apart, will be required to be considered negative. Both natural clearers and those who have cleared HCV on antiviral therapy are eligible.;
  5. Serological evidence of HIV-1;
  6. Evidence of liver dysfunction (persistently elevated alanine aminotransaminase, aspartate aminotransferase, bilirubin >1.5 x upper limit of normal);
  7. Platelet count <50 x 109/L;
  8. Uncontrolled glaucoma, diabetes mellitus, or hypertension;
  9. Malignancy requiring treatment;
  10. Patients with uncontrolled cardiac failure, unstable angina or myocardial infarction in the past 6 months;
  11. Poor performance status (World Health Organization score >1);
  12. Prior treatment with any gene transfer medicinal product;
  13. Known or suspected intolerance, hypersensitivity or contraindication to the investigational product and non-investigational medicinal products or their excipients;
  14. Planned major elective surgery prior to the end of trial.
  15. Current or relavant history of a physical or psychiatric illness or any medical condition that in the opinion of the investigator could affect the patients safety or interfere with the study assessments.
  16. CMV IgG postive patients who are CMV PCR positive at screening.

Sites / Locations

  • St Jude Children's Research Hospital
  • St James's Hospital
  • University of Milan
  • Basingstoke Haemostasis and Thrombosis Centre
  • East Kent Hospitals University
  • Guy's and St Thomas's NHS Foundation Trust
  • Royal Free Hospital
  • Newcastle Hospitals NHS Trust
  • Oxford University Hospital
  • University of Sheffield
  • University Hospital Southampton

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

FLT180a, 6x10e^11 vg/kg solution for infusion

FLT180a, 2 x 10e^12 vg/kg solution for infusion

FLT180a, 1x10e^12 vg/kg solution for infusion

FLT180a, 1.3x10e^12 vg/kg solution for infusion

Arm Description

Participants receiving gene therapy vector at a dose of 6x10e^11 vg/kg

Participants receiving gene therapy vector at a dose of 2 x 10e^12 vg/kg

Participants receiving gene therapy vector at a dose of 1 x 10e^12 vg/kg

Participants receiving gene therapy vector at a dose of 1.3 x 10e^12 vg/kg

Outcomes

Primary Outcome Measures

Frequency and Severity of Treatment-emergent Adverse Events (TEAEs) (Safety)
Safety as assessed by the reporting of AEs according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0
Number of Participants With FIX Activity Response
The proportion of participants at the terminal dose (1.3 x 10e^12 vg/kg) achieving clinical FIX response and proportion of patients achieving normalised FIX response at Week 26. A clinical FIX response is defined as achieving a FIX activity of 5% to 150%. Normalised FIX response is defined as achieving FIX activity in the normal range (50-150%).

Secondary Outcome Measures

Number of Participants With a Change From Baseline or Abnormal Finding From Routine Safety Assessments
Safety as assessed by reporting of abnormal or change from baseline findings from routine safety assessments including, laboratory assessments, ECG, physical exam and liver ultrasound.
FIX Concentrate Usage
Change from baseline in FIX concentrate consumption.
Bleeding Frequency
Change from baseline in annualised bleeding rate (ABR)
Immune Response - Development of Inhibitors
Immune response to the human FIX transgene product (i.e., development of FIX neutralising antibodies referred to as inhibitors) will be assessed by measurement of the level of inhibitors.
Viral Shedding Evaluated as Time to Unquantifiable Vector Genomes
Serum and bodily secretions will be collected to assess clearance of vector genomes
Endogenous FIX Production
The proportion of patients achieving FIX activity at or above 5%, 15%, 30%, 40%, 50%, 70% and 150% of normal, at each scheduled visit, will be summarised by dose and overall.
Change From Baseline in FIX Activity as a Percentage of Normal Values
Absolute change from baseline in FIX production (% FIX activity) at week 26/EOS will be summarised.

Full Information

First Posted
September 13, 2017
Last Updated
November 8, 2022
Sponsor
University College, London
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1. Study Identification

Unique Protocol Identification Number
NCT03369444
Brief Title
A Factor IX Gene Therapy Study (FIX-GT)
Acronym
FIX-GT
Official Title
A Phase I/II, Open Label, Multicentre, Ascending Single Dose, Safety Study of a Novel Adeno- Associated Viral Vector (FLT180a) in Patients With Haemophilia B
Study Type
Interventional

2. Study Status

Record Verification Date
November 2022
Overall Recruitment Status
Terminated
Why Stopped
Terminated early due to challenges during the COVID-19 pandemic and a change in requirements of data to be submitted for marketing authorisation.
Study Start Date
December 5, 2017 (Actual)
Primary Completion Date
October 20, 2020 (Actual)
Study Completion Date
October 20, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University College, London

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Severe haemophilia B (HB) is a bleeding disorder where a protein made by the body to help make blood clot is either partly or completely missing. This protein is called a clotting factor; with severe haemophilia B, levels of clotting factor IX (FIX) (nine) are very low and affected individuals can suffer life threatening bleeding episodes. HB mainly affects boys and men (normally one in every 30,000 males). Current treatment for HB involves intravenous infusions of factor IX as regular treatment (Prophylaxis) or 'on demand'. On demand treatment is highly effective at stopping bleeding but cannot fully reverse long-term damage that follows after a bleed. Regular treatment can prevent bleeding, however can be invasive for patients and also expensive. This research study aims to test the safety and effectiveness of a gene therapy which produces Factor IX protein in the body. The gene will be given using an inactivated virus called "the vector" ( FLT180a), in a single infusion. The vector has been developed from a virus known as an adeno- associated virus, that has been changed so that it is unable to cause a viral infection in humans. This "inactivated" virus is further altered to carry the Factor IX gene and to make its way within liver cells where Factor IX protein is normally made. Up to three different doses cohorts of FLT180a will be tested, in up to 24 patients with severe haemophilia B. Patients will be recruited from haemophilia centres in the EU and US. Patients will be in the trial for approximately 40 weeks and will undergo procedures including physical examinations, bloods tests, ECGs and liver ultrasounds.
Detailed Description
This was a Phase I/II, open-label, multicentre, ascending single-dose, safety study of FLT180a in patients with severe (FIX activity <1%) or moderately severe (FIX activity 1% to 2% with severe bleeding phenotype) HB. Up to 24 patients were planned to be enrolled; however, the study was terminated early (on 20 October 2020) after 10 patients had been enrolled because of changes to the clinical development plan and recruitment difficulties due to the COVID-19 pandemic. Patients who provided consent to participate and had historical data on bleeding and FIX consumption documented from the previous 3 years' medical notes were screened for eligibility in this study. During the screening period, patients completed a diary to prospectively record ongoing bleeding events and FIX consumption. Patients were monitored through a comprehensive schedule of safety assessments at outpatient visits for 26 weeks. On completion of the study, patients are to be followed for 15 years under a separate long term follow-up protocol. Patients who provided consent to participate in this study underwent screening assessments up to 52 weeks before study Day 0 (FLT180a infusion). Due to the risk of bleeding in this patient population, a washout from the patient's FIX concentrate regimen was not mandated. The investigator was to demonstrate, from the patient's medical records, a documented FIX activity level of <1% for severe patients or <2% for moderately severe patients. If (at the investigator's discretion) a FIX concentrate washout was undertaken during the screening period, a minimum of 5 days' washout was required. Treatment-eligible patients reported to the study site on the day before receiving the gene therapy infusion (Day 1). On Day 0, FLT180a was administered as a single dose, slow intravenous (IV) infusion into a peripheral vein. The patient remained in the study centre for ≥12 hours and until the investigator deemed the patient fit to be discharged. The first 2 patients treated at each dose level remained at the study centre for 24 hours after infusion before discharge. Patients who were on prophylactic therapy with FIX concentrates remained on their usual dosing schedule and were closely monitored for FIX activity levels after screening and administration of FLT180a. If FIX activity levels ≥3% were reached, then prophylaxis was held pending a repeat analysis within a period of 72 hours. If the FIX activity levels were ≥3% at that time, then prophylaxis was stopped with continued/regular assessment of FIX activity levels and occurrence of spontaneous bleeding. Patients were required to undergo study evaluations at intervals over the 26-week, post-treatment period. These evaluations took place either at the study infusion site or at their normal haemophilia treatment centre. To monitor for shedding of vector genome (vg) sequences, patients were required to provide plasma, saliva, urine, stool, and semen samples until the results of 3 successive samples were clear. This was a first-in-human study; therefore, an ascending-dose design was implemented to enable dose evaluation in a step-wise manner. Three dose cohorts of vector (low, intermediate, and high) were tested in the dose escalation. Two patients were tested at each dose level with an additional patient added in the event of a dose limiting toxicity (DLT) (2 + 1 design). Dose escalation occurred provided there was no more than 1 DLT at any dose cohort and if the resulting FIX activity failed to reach the target level. A reduction of the dose level within a cohort occurred if the FIX activity exceeded defined levels to reduce the risk of exceeding the normal physiological range. A dose reduction occurred when the 2 + 1 design was applied at that new dose level within the cohort. At the discretion of the Sponsor after advice from the trial management group (TMG) and independent data monitoring committee (DMC), additional patients were to be added to any cohort to ensure adequate characterisation of either safety or the FIX response before dose escalation/reductions. The Sponsor, TMG, and DMC planned to select the terminal dose level based on the patient FIX activity levels with the aim of ensuring most patients reached a FIX activity level within normal limits and in the absence of DLTs; the terminal dose level was planned to be expanded to 14 patients, but never reached. This design minimised the number of patients who would need to be dosed at suboptimal levels while allowing evaluation of safety with the option to expand a group on observation of DLTs. An extended 6-week interval was observed between the first and second patient on study to monitor for any unanticipated, delayed adverse events (AEs). Subsequently, when dose escalation was ongoing, the study mandated a minimum 4-week interval between patients during which time efficacy and safety was reviewed before a decision to dose the next patient. The main risk in this study was a dose-dependent, asymptomatic increase in the serum alanine aminotransferase (ALT) level associated with a decline in FIX levels, suggesting a loss of transduced hepatocytes. In this study, all patients were given a take-home pack of immunosuppressants (prednisolone only) to be taken under the direction of the investigator, which allowed rapid intervention if transaminase elevations were observed. In addition, during the anticipated critical time period all patients were to receive a course of immunosuppressants (prednisolone, methylprednisolone, and tacrolimus) beginning at the Week 3 visit or Week 4 visit in line with the relevant protocol version active at the time. The main efficacy endpoint was based on an analysis of the proportion of patients achieving a clinical or normalised FIX response at 26 weeks. A clinical FIX response was defined as achieving a FIX activity of 5% to 150% of normal. Five percent had been selected as the threshold for a clinical FIX response because using gene therapy in patients with HB to increase FIX activity from <1% to 5% had previously been shown to lead to a highly clinically significant improvement in annualised bleeding rates (ABR) and exogenous factor consumption. A normalised FIX response was defined as achieving a FIX activity level in the normal range (50% to 150%). The normal range had been selected as the threshold level for a normalised FIX response because reaching this level was expected to modify the patient phenotype from severe at study start to normal at which point patients would not be expected to experience spontaneous bleeds. The choice of a 26-week endpoint was based on previous experience with Adeno-Associated Virus (AAV) gene therapy for HB in which patients achieved steady-state FIX levels by 16 weeks after gene therapy. Based on this, it was anticipated that the patients' FIX activity would reach a stable level by 26 weeks, thus this was an appropriate point at which to measure activity.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hemophilia B

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
10 (Actual)

8. Arms, Groups, and Interventions

Arm Title
FLT180a, 6x10e^11 vg/kg solution for infusion
Arm Type
Experimental
Arm Description
Participants receiving gene therapy vector at a dose of 6x10e^11 vg/kg
Arm Title
FLT180a, 2 x 10e^12 vg/kg solution for infusion
Arm Type
Experimental
Arm Description
Participants receiving gene therapy vector at a dose of 2 x 10e^12 vg/kg
Arm Title
FLT180a, 1x10e^12 vg/kg solution for infusion
Arm Type
Experimental
Arm Description
Participants receiving gene therapy vector at a dose of 1 x 10e^12 vg/kg
Arm Title
FLT180a, 1.3x10e^12 vg/kg solution for infusion
Arm Type
Experimental
Arm Description
Participants receiving gene therapy vector at a dose of 1.3 x 10e^12 vg/kg
Intervention Type
Biological
Intervention Name(s)
FLT180a
Intervention Description
FLT180a is a replication-incompetent adeno- associated viral vector. The vector is composed of a DNA vector genome encapsidated in an adeno-associated virus derived protein capsid. The expression cassette contains DNA encoding Factor IX.
Primary Outcome Measure Information:
Title
Frequency and Severity of Treatment-emergent Adverse Events (TEAEs) (Safety)
Description
Safety as assessed by the reporting of AEs according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0
Time Frame
From Day 0 (first dose of FLT180a) until week 26 post infusion (up to 26 weeks)
Title
Number of Participants With FIX Activity Response
Description
The proportion of participants at the terminal dose (1.3 x 10e^12 vg/kg) achieving clinical FIX response and proportion of patients achieving normalised FIX response at Week 26. A clinical FIX response is defined as achieving a FIX activity of 5% to 150%. Normalised FIX response is defined as achieving FIX activity in the normal range (50-150%).
Time Frame
From screening until week 26 post infusion (Up to 38 weeks)
Secondary Outcome Measure Information:
Title
Number of Participants With a Change From Baseline or Abnormal Finding From Routine Safety Assessments
Description
Safety as assessed by reporting of abnormal or change from baseline findings from routine safety assessments including, laboratory assessments, ECG, physical exam and liver ultrasound.
Time Frame
From screening until week 26 post infusion (Up to 38 weeks)
Title
FIX Concentrate Usage
Description
Change from baseline in FIX concentrate consumption.
Time Frame
Baseline and Post Dose (Day15 post infusion to Week26/End of Study)
Title
Bleeding Frequency
Description
Change from baseline in annualised bleeding rate (ABR)
Time Frame
Baseline and Post-Dose (Day 15 to Week 26/EOS)
Title
Immune Response - Development of Inhibitors
Description
Immune response to the human FIX transgene product (i.e., development of FIX neutralising antibodies referred to as inhibitors) will be assessed by measurement of the level of inhibitors.
Time Frame
Week 1, week 2, week 3, week 6, week 9, week 12, week 16, week 20 and week 26/EOS post infusion
Title
Viral Shedding Evaluated as Time to Unquantifiable Vector Genomes
Description
Serum and bodily secretions will be collected to assess clearance of vector genomes
Time Frame
From screening until time to unquantifiable results of vector genomes in all matrices, up to an average of 5.14 weeks
Title
Endogenous FIX Production
Description
The proportion of patients achieving FIX activity at or above 5%, 15%, 30%, 40%, 50%, 70% and 150% of normal, at each scheduled visit, will be summarised by dose and overall.
Time Frame
From screening until week 26 post infusion
Title
Change From Baseline in FIX Activity as a Percentage of Normal Values
Description
Absolute change from baseline in FIX production (% FIX activity) at week 26/EOS will be summarised.
Time Frame
Week 26/EOS

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Adults males, ≥ 18 years of age. Confirmed diagnosis of HB defined as one of the following: Documented severe FIX deficiency with plasma FIX activity of <1% of normal, or moderately severe FIX deficiency with plasma FIX activity level between ≥1% and ≤2% and a severe bleeding phenotype defined by one of the following: i. On prophylaxis for a history of bleeding, or ii. On demand therapy with a history of 4 or more bleeding episodes/year on average over the past 3 years, or iii. evidence of chronic haemophilic arthropathy (pain, joint destruction, and loss of range of motion). Able to give full informed consent and able to comply with all requirements of the trial including 15-year long-term follow-up. Willing to practice barrier contraception until at least 3 consecutive semen samples after vector administration are negative for vector sequences. Lack of neutralising anti-AAV-S3 antibodies using an in vivo transduction inhibition assay within 4 weeks of vector administration. At least 150 exposure days to FIX concentrates. Exclusion Criteria: Presence of neutralising anti-human FIX antibodies (inhibitor, determined by the Bethesda inhibitor assay) at the time of enrolment or a previous history of FIX inhibitor; Patients at high risk of thromboembolic events (high risk patients would include those with a history of arterial or venous thromboembolism (e.g. deep vein thrombosis, pulmonary embolism, non-haemorrhagic stroke, arterial embolus) and those with acquired thrombophilia including conditions such as atrial fibrilation); Use of investigational therapy for haemophilia within 30 days before enrolment; Patients with active hepatitis B or C, and hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) Ribonucleic acid (RNA) viral load positivity, respectively, or currently on antiviral therapy for hepatitis B or C. Negative viral assays in 2 samples, collected at least 6 months apart, will be required to be considered negative. Both natural clearers and those who have cleared HCV on antiviral therapy are eligible.; Serological evidence of human immunodeficiency virus (HIV-1); Evidence of liver dysfunction (persistently elevated alanine aminotransaminase, aspartate aminotransferase, bilirubin >1.5 x upper limit of normal); Platelet count <50 x 109/L; Uncontrolled glaucoma, diabetes mellitus, or hypertension; Malignancy requiring treatment; Patients with uncontrolled cardiac failure, unstable angina or myocardial infarction in the past 6 months; Poor performance status (World Health Organization score >1); Prior treatment with any gene transfer medicinal product; Known or suspected intolerance, hypersensitivity or contraindication to the investigational product and non-investigational medicinal products or their excipients; Planned major elective surgery prior to the end of trial. Current or relevant history of a physical or psychiatric illness or any medical condition that in the opinion of the investigator could affect the patients safety or interfere with the study assessments. Cytomegalovirus (CMV) Immunoglobulin G (IgG) positive patients who are CMV PCR positive at screening.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Pratima Chowdary
Organizational Affiliation
University College London / Royal Free London NHS Foundation Trust
Official's Role
Principal Investigator
Facility Information:
Facility Name
St Jude Children's Research Hospital
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38119
Country
United States
Facility Name
St James's Hospital
City
Dublin
Country
Ireland
Facility Name
University of Milan
City
Milan
Country
Italy
Facility Name
Basingstoke Haemostasis and Thrombosis Centre
City
Basingstoke
Country
United Kingdom
Facility Name
East Kent Hospitals University
City
Canterbury
Country
United Kingdom
Facility Name
Guy's and St Thomas's NHS Foundation Trust
City
London
Country
United Kingdom
Facility Name
Royal Free Hospital
City
London
Country
United Kingdom
Facility Name
Newcastle Hospitals NHS Trust
City
Newcastle Upon Tyne
Country
United Kingdom
Facility Name
Oxford University Hospital
City
Oxford
Country
United Kingdom
Facility Name
University of Sheffield
City
Sheffield
Country
United Kingdom
Facility Name
University Hospital Southampton
City
Southampton
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
35857660
Citation
Chowdary P, Shapiro S, Makris M, Evans G, Boyce S, Talks K, Dolan G, Reiss U, Phillips M, Riddell A, Peralta MR, Quaye M, Patch DW, Tuddenham E, Dane A, Watissee M, Long A, Nathwani A. Phase 1-2 Trial of AAVS3 Gene Therapy in Patients with Hemophilia B. N Engl J Med. 2022 Jul 21;387(3):237-247. doi: 10.1056/NEJMoa2119913.
Results Reference
derived

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A Factor IX Gene Therapy Study (FIX-GT)

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